Marked Prevention of Ischemic Brain Injury by Neu2000, an NMDA Antagonist and Antioxidant Derived from Aspirin and Sulfasalazine

Abstract

Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxicischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 lmol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.

Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat

“…-induced free radical toxicity at 300 nM in cultured cortical neurons [18]. Administration of Neu2000 (50 mg/kg, ip) significantly blocked MFR production in CA1 neurons 2 h and 2 days after TFI (Fig.…”

Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats

“…Administration of deferoxamine mesylate (DFO) (200 mg/kg; s.c.), a selective iron chelator, or Neu2000 (50 mg/kg, i.p. ), a potent spin trapping molecule derived from aspirin and sulfasalazine (Gwag et al, 2007) immediately after reperfusion, almost completely blocked TFI-induced MFRs production 2 h after TFI ( Figure 3C). …”

N-Stearoyltyrosine Protects Against Glutamate-Induced Oxidative Toxicity by an Apoptosis-Inducing Factor (AIF)-Mediated Caspase-Independent Cell Death Pathway

“…Agents with the potential to intervene in multiple injuries would offer a novel therapeutic strategy for stroke/cerebral ischemia (4,5). Endocannabinoid AEA can protect neurons from damages through intervening in multiple injuries, such as inhibiting glutamate release (19 -21), scavengering free radicals (6,22,23), reduc ing Ca 2+ influx (24,25), and decreasing inflammatory response (8).…”

“…The pharmaceutical approaches intervening in multiple injuries instead of a single injury may function effec tively for multifaceted neuronal death in stroke/cerebral ischemia patients (4,5). Endocannabinoid anandamide (AEA) has been reported to protect neurons from ischemic injury via intervening in multiple injuries (6 -8).…”